Auxilium Pharmaceuticals, Inc., a specialty biopharmaceutical company, announced positive data for collagenase clostridium histolyticum or CCH which is being developed for the potential treatment, if approved by the US Food and Drug Administration (FDA), of adult patients with adhesive capsulitis (AC), commonly known as frozen shoulder syndrome (FSS).  

FSS is a common, prolonged, painful condition of the shoulder in which increased capsular collagen thickening and subsequent capsular contraction in the shoulder joint is thought to cause a loss of range of motion in the shoulder.  The condition is believed to affect approximately two to five percent of the general adult population and the full duration of the disease can last from approximately 1 year to up to 3.5 years.   The majority of cases are currently managed conservatively with prolonged physical therapy and occasionally with steroid injections.   It is estimated that approximately 300,000 cases of FSS are diagnosed annually and approximately 10 per cent are treated with an invasive intervention (surgery or manipulation under anaesthesia) on an annual basis.

"Positive top-line data from our phase IIa Frozen Shoulder Syndrome clinical trial represent another very encouraging development milestone for Auxilium as we advance a fourth potential indication of CCH, further diversifying our evolving pipeline," explained Adrian Adams, chief executive officer and president of Auxilium. "We believe Frozen Shoulder syndrome represents a condition with few optimal treatment strategies and no approved therapies.  Innovative approaches such as CCH may, if approved by the FDA, allow affected patients quicker relief from limits in range of motion and associated pain."

The phase IIa study was an open-label, controlled dose-ranging study designed to assess the safety and efficacy of CCH for the treatment of Stage 2 unilateral idiopathic FSS in comparison to an exercise-only control group. The study involved 50 adult men and women at 11 sites throughout the US.  Four cohorts of 10 patients each received up to three ultrasound-guided extra articular injections of varying doses of CCH (ranging from 0.29 mg to 0.58 mg in three different volumes; 0.5, 1.0, or 2.0 mL), separated by a minimum of 21 days.  All patients were instructed to perform home shoulder exercises. The fifth cohort of ten patients received no CCH injections and only performed home shoulder exercises. The study's primary endpoint was the change (in degrees) from baseline to the day 92 follow-up in active forward flexion in the affected shoulder compared to the exercise-only cohort.  Safety assessments were made during all study visits and immunogenicity testing was performed at screening and day 92.

Both the 0.58mg(1mL) and 0.58mg(2mL) dosing arms showed positive, statistically significant improvement from baseline in forward flexion vs. the exercise-only group.  The 0.58mg(1mL) dosing arm also showed statistically significant improvement from baseline in shoulder abduction vs. the exercise-only group.  Positive trends with improvement in degrees were also seen in other active range of motion (AROM) assessments vs. the exercise-only group.  Twenty-nine study patients (72.5%) received three CCH injections with 5 subjects receiving two injections and 6 subjects receiving one injection only.

Patients were also assessed using the American Shoulder and Elbow Surgeons (ASES) Scale for function and pain.  Both the 0.58 mg(1mL) and 0.58 mg(2mL) cohort demonstrated statistically significant improvement in pain and function over baseline scores vs. the exercise-only group (p<0.05).  

"We are very pleased with study results demonstrating a dose response with CCH, significant improvement in multiple range of motion measurements and a well-tolerated safety profile in this phase IIa study," said Dr. James Tursi, chief medical officer of Auxilium. "We look forward to advancing the clinical development of CCH in Frozen Shoulder syndrome and are currently assessing options to determine the safest and optimal path forward in development."

Treatment-related adverse events with CCH were mostly localized bruising, injection site pain and swelling, hematoma, and musculoskeletal pain.  All such events resolved without intervention, and are consistent with XIAFLEX/CCH use in other approved and potential indications.  No subjects discontinued the study due to an adverse event.  A shoulder MRI was performed on all patients at screening and day 92.  Screening MRIs were performed to exclude the presence of other clinically significant conditions such as concomitant rotator cuff injury.  Day 92 MRI evaluations indicated there were no rotator cuff injuries.  There were no drug-related serious adverse events reported.

FSS, also known as adhesive capsulitis, is a common, prolonged, and painful disorder of diminished shoulder motion.  The full duration of the frozen stage of disease can last from 1 to 3.5 years with a mean of 30 months.  Increased capsular collagen thickening and subsequent capsular contraction in the glenohumeral joint is thought to cause restriction in both active and passive range of motion in the shoulder.   As the condition progresses, pain can become more severe and is accompanied by stiffness and decreased range of motion. The stiffening may increase to the point where the natural arm swing that accompanies normal gait is lost.   The most common treatments for FSS are long-term intensive physical therapy, corticosteroids, manipulation under anaesthesia and/or arthroscopic release, but the long-term outcomes literature uses varying endpoints and each treatment has differing associated risks. Drugs are often used to manage associated pain, but none have been demonstrated to have an impact on FSS.

FSS is estimated to affect approximately two to five percent of the general adult population1 and has an increased incidence among patients with diabetes,  Dupuytren's contracture, and thyroid disease. It tends to occur in a patient's fourth to sixth decade of life.  The condition occurs slightly more often in women than in men, often presents bilaterally and commonly affects the contralateral side years after onset of symptoms in the first shoulder, but it does not typically affect the same shoulder twice.1

Xiaflex (collagenase clostridium histolyticum or CCH) is a biologic approved in the US, EU and Canada for the treatment of adult Dupuytren's contracture patients with a palpable cord. Xiaflex is a minimally invasive treatment for this condition and consists of a highly purified combination of subtypes of collagenase, derived from Clostridium histolyticum, in a specific proportion. Together, the collagenase sub-types work synergistically to break the bonds of the triple helix collagen structure more effectively than each collagenase alone. Xiaflex  is currently under review by the FDA for the treatment of Peyronie's disease.  CCH is also in phase II of development for the treatment of cellulite (edematous fibrosclerotic panniculopathy).

The phase IIa study was an open-label, controlled dose-ranging study designed to assess the safety and efficacy of CCH for the treatment of FSS in comparison to an exercise-only control group.  The study involved 50 adult men and women at multiple sites throughout the US.

To qualify for the FSS study, patients must have had Stage 2 unilateral idiopathic adhesive capsulitis of the shoulder with restricted range of motion in the affected shoulder for at least three months, but not more than 12 months.